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A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model

¹ Molecular Oncology Program and ² High Throughput Screening and Chemistry Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: W. Douglas Cress, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-6703; Fax: 813-745-7264; E-mail: douglas.cress{at}moffitt.org.

Key Words: E2F • melanoma

HLM006474 was identified using a computer-based virtual screen and the known crystal structure of the DNA-bound E2F4/DP2 heterodimer. Treatment of multiple cell lines with HLM006474 resulted in the loss of intracellular E2F4 DNA-binding activity as measured by electrophoretic mobility shift assay within hours. Overnight exposure to HLM006474 resulted in down-regulation of total E2F4 protein as well as known E2F targets. The effects of HLM006474 treatment on different cell lines varied but included a reduction in cell proliferation and an increase in apoptosis. HLM006474 induced apoptosis in a manner distinct from cisplatin and doxorubicin. E2F4-null mouse embryonic fibroblasts were less sensitive than wild-type counterparts to the apoptosis-inducing activity of the compound, revealing its biological specificity. A375 cells were extremely sensitive to the apoptosis-inducing activity of the compound in two-dimensional culture, and HLM006474 was a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system. Together, these results suggest that interference with E2F activity using small molecules may have clinical application in cancer therapy. [Cancer Res 2008;68(15):6292–9]

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